TY - JOUR
T1 - Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6
AU - Unno, Toshinori
AU - Wakamori, Minoru
AU - Koike, Masato
AU - Uchiyama, Yasuo
AU - Ishikawa, Kinya
AU - Kubota, Hisahiko
AU - Yoshida, Takashi
AU - Sasakawa, Hiroko
AU - Peters, Christoph
AU - Mizusawa, Hidehiro
AU - Watase, Kei
PY - 2012/10/23
Y1 - 2012/10/23
N2 - Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by the expansion of a polyglutamine tract in the Cav2.1 voltage-gated calcium channel. To elucidate how the expanded polyglutamine tract in this plasma membrane protein causes the disease, we created a unique knockin mouse model that modestly overexpressed the mutant transcripts under the control of an endogenous promoter (MPI-118Q). MPI-118Q mice faithfully recapitulated many features of SCA6, including selective Purkinje cell degeneration. Surprisingly, analysis of inclusion formation in the mutant Purkinje cells indicated the lysosomal localization of accumulated mutant Cav2.1 channels in the absence of autophagic response. The lack of cathepsin B, a major lysosomal cysteine proteinase, exacerbated the loss of Purkinje cells and was accompanied by an acceleration of inclusion formation in this model. Thus, the pathogenic mechanism of SCA6 involves the endolysosomal degradation pathway, and unique pathological features of this model further illustrate the pivotal role of protein context in the pathogenesis of polyglutamine diseases.
AB - Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by the expansion of a polyglutamine tract in the Cav2.1 voltage-gated calcium channel. To elucidate how the expanded polyglutamine tract in this plasma membrane protein causes the disease, we created a unique knockin mouse model that modestly overexpressed the mutant transcripts under the control of an endogenous promoter (MPI-118Q). MPI-118Q mice faithfully recapitulated many features of SCA6, including selective Purkinje cell degeneration. Surprisingly, analysis of inclusion formation in the mutant Purkinje cells indicated the lysosomal localization of accumulated mutant Cav2.1 channels in the absence of autophagic response. The lack of cathepsin B, a major lysosomal cysteine proteinase, exacerbated the loss of Purkinje cells and was accompanied by an acceleration of inclusion formation in this model. Thus, the pathogenic mechanism of SCA6 involves the endolysosomal degradation pathway, and unique pathological features of this model further illustrate the pivotal role of protein context in the pathogenesis of polyglutamine diseases.
KW - Cerebellum
KW - Inherited ataxia
KW - P/Q-type calcium channel
UR - http://www.scopus.com/inward/record.url?scp=84867908880&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867908880&partnerID=8YFLogxK
U2 - 10.1073/pnas.1212786109
DO - 10.1073/pnas.1212786109
M3 - Article
C2 - 23054835
AN - SCOPUS:84867908880
VL - 109
SP - 17693
EP - 17698
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 43
ER -